3',4'-Dideoxykanamycin A of formula (III), which was first prepared semi-synthetically from kanamycin A by H. Umezawa et al. (Japanese Patent KOKAI No. 105699/80; Belgian Pat. No. 881251; U.S. Pat. No. 4,195,170; U.S. patent application Ser. No. 187,014), and 4'-deoxykanamycin A of formula (IV), which was first prepared semi-synthetically from kanamycin A by Naito et al. (Japanese Patent KOKAI No. 93944/75; U.S. Pat. No. 3,886,138), are known to exhibit an improved anti-bacterial activity against kanamycin-sensitive and -resistant organisms, as compared with kanamycin A. However, both the methods referred to above require many steps to obtain suitably protected derivatives of kanamycin A which possess only the objective hydroxyl group free. In both the methods, it was necessary, in order to obtain the protected kanamycin A derivatives containing the free 4'-hydroxyl group, to take complicated preparatory steps. Thus the 6'-amino group of kanamycin A was protected with an amino-protecting group and the other amino groups were protected with another protecting group. After the formation of 4',6'-O,N-cyclic carbamate with a base, the hydroxyl groups which are not to be removed were protected with a hydroxyl-protecting group. After the subsequent ring-opening of the carbamate, the 6'-amino group was again protected with an amino-protecting group.
General deoxygenation procedure, which is elegantly applied for the preparation of 3',4'-dideoxykanamycin B and tobramycin from kanamycin B via their sulfonyl derivatives, is not suitable for kanamycin A derivative because the protecting steps prior to the deoxygenation are very complicated.
We have investigated the application of the new process proposed by use for the preparation of 3',4'-dideoxykanamycin B (Japanese Patent KOKAI No. 71445/77; U.K. Pat. No. 1,537,905) to the preparation of deoxy derivatives of kanamycin A. The process disclosed in this publication is based on taking advantage of a behavior of saccharide in an acylation reaction that the reactivity of the 4-hydroxyl group is markedly lower than that of any other hydroxyl group thereof and comprises reacting 4",6"-O-protected derivative of penta-N-protected kanamycin B with an alkanoyl chloride or aroyl chloride, typically benzoyl chloride, in pyridine to acylate the 3'- and 2"-hydroxyl groups to leave the 4'-hydroxyl group free. Sulfonylation of the 4'-hydroxyl group of the acylated derivative gives a compound of formula (V): ##STR4## wherein R' represents an alkyl or aryl group; W' represents a mesyl, tosyl or benzylsulfonyl; X' represents an alkanoyl group, typically those containing 2-4 carbon atoms such as acetyl or an aroyl group, typically benzoyl; and Y' represents an alkylidene, aralkylidene, cycloalkylidene or tetrahydropyranylidene group. Treatment of the resulting compound with an alkali metal alcoholate in a lower alkanol under alkaline conditions affords the 3',4'-anhydro-4'-epi derivative of kanamycin B of formula (VI): ##STR5## wherein R' and Y' have the same meanings as defined above, as an intermediate with a high yield in a relatively small number of steps.
The difference in chemical structure between kanamycin B and kanamycin A resides in that the former has an amino group in the 2'-position, whereas the latter has a hydroxyl group in that position. We have now found that kanamycin A can be converted to 3',4'-anhydro-4'-epi derivative by the following method. Firstly, all the four amino groups of kanamycin A are protected with an amino-protecting group. After the reaction of the tetra-N-protected kanamycin A with a divatent hydroxyl-protecting reagent, the resulting 4",6"-O-protected derivative is treated with an alkanoyl halide or aroyl halide, typically benzoyl halide, to acylate the 2'-, 3'- and 2"-hydroxyl groups and to leave the 4'-hydroxyl group free without acylation, followed by the sulfonylation of the 4'-hydroxyl group and the treatment of the sulfonylated derivative thus formed with an alkali metal alcoholate in an alkanol. The resulting 3',4'-anhydro-4'-epi derivative can be converted to 3',4'-dideoxykanamycin A in a manner known per se.